Endovascular perfusion augmentation for critical care

ABSTRACT

Systems and methods for Endovascular Perfusion Augmentation for Critical Care (EPACC) are provided. The system may include a catheter having an expandable aortic blood flow regulation device disposed on the distal end of the catheter for placement within an aorta of a patient. The system may also include a catheter controller unit that causes the expandable aortic blood flow regulation device to expand and contract to restrict blood flow through the aorta. The system may also include one or more sensors for measuring physiological information indicative of blood flow through the aorta, and a non-transitory computer readable media having instructions stored thereon, wherein the instructions, when executed by a processor coupled to the one or more sensors, cause the processor to compare the measured physiological information with a target physiological range associated with blood flow through the aorta such that the catheter controller unit automatically adjusts expansion and contraction of the expandable aortic blood flow regulation device to adjust an amount of blood flow through the aorta if the measured physiological information falls outside the target physiological range.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Patent ApplicationNo. PCT/US2018/013413, filed Jan. 11, 2018, which claims priority toU.S. Provisional Application Ser. No. 62/445,551, filed Jan. 12, 2017,the disclosures of which are herein incorporated by reference in theirentirety for all purposes.

STATEMENT OF GOVERNMENT INTEREST

This invention was made with Government support under Grant No.HL108964, awarded by the National Institutes of Health (NIH). TheGovernment has certain rights in the invention.

FIELD OF USE

The present disclosure relates generally to endovascular aortic flowregulation devices deployed within the aorta. More particularly, theinvention relates to systems and methods for endovascular perfusionaugmentation for critical care.

BACKGROUND

Death from the complications of shock continues to exist as a highprobability in an overwhelming number of cases in both medical andsurgical patients. Existing systems, medications, and procedures used totreat shock states frequently contribute to a patient's ultimate deaththrough inability to maintain adequate oxygen delivery to vital organs.This delivery of oxygen is predicated on adequate blood perfusion to theorgans. It is well recognized that without sufficient blood pressure tothe heart and lungs hemodynamic collapse ensues resulting in decreasedperfusion to the remaining organs and eventual death.

Restoring homeostasis for a patient in shock is difficult and laborintensive. The dynamic nature of the patient's physiology after a severeinitial insult requires both medical expertise as well as continuousappraisal and modification to the care provided. Yet, for all thesophistication and innovation of modern medicine, the current “state ofthe art” in critical care medicine remains a fairly imprecise “one sizefits all” resuscitation and critical care strategy. The resuscitation ofa patients suffering from shock, whether neurogenic, hemorrhagic,hypovolemic, or septic, poses unique challenges especially during theearly hours of critical care. Any episodes of hypotension can bedetrimental to the patient. Older patients, as well as patients who havesuffered a traumatic brain injury are especially susceptible to episodesof hypotension.

Current practice to treat shock is dependent upon the etiology, butalmost all treatment algorithms include intravenous (IV) fluids or bloodproducts and, when necessary, titration of vasoactive medications thatact upon the vasculature to cause vasoconstriction and an increase inblood pressure. For example, the primary focus in hemorrhagic shock isaggressive transfusion of blood products in roughly the same amounts andcomposition of the blood that was lost. Likewise, in sepsis andischemia-reperfusion injuries, resuscitation is initiated with large IVcrystalloid boluses irrespective of the underlying pathophysiology.However, in these instances, and many other critical care scenarios, thedoses of fluid and vasopressors are approximations and the endpoints arefairly subjective. Thus, modern shock resuscitation is still notprecisely targeted towards the physiologic demands of the individualpatient. This lack of precision ultimately arises from the inability toefficiently analyze the efficacy of care in real time, e.g.,second-to-second and minute-to-minute, and provide rapid adjustments inresponse to a critically ill patient's physiology.

For example, although the nuances of treating shock are dependent uponetiology, all treatment modalities suffer from similar drawbacks. First,IV fluids are often required in large amounts early on during treatmentto improve blood pressure. At times, the volume of fluid can be so greatthat it overwhelms the cardiovascular system resulting in pulmonaryedema, ARDS, or heart failure. Therefore, although often required earlyon in treatment, alternative methods to remove this excess fluid areoften required as soon as the patient can tolerate diuresis.

A second complication from current therapies is the secondaryconsequences of high doses of vasopressor medications. Vasopressors actdirectly on the blood vessels to increase vascular tone and improvesystemic blood pressure. In the absence of a better therapeuticsolution, these medications are at times necessary to improve perfusionto vital organs. However, this systemic increase in blood pressure doescome at the potential cost of poor perfusion at the microvascular level.Unfortunately, due to differential responses to these medications acrossorgans and tissue beds, unpredictable changes in regional blood flow canoccur, which may ultimately have a counterproductive or detrimentaleffect. With high doses of these medications, certain tissues may incurpermanent injury such as the distal extremities, potentiallynecessitating major limb amputation. In patients suffering fromtraumatic brain injury with increased intracranial pressure, studies inanimals and in humans have demonstrated that high doses of vasopressorsare often able to improve perfusion to the injured areas of the brain,but often at the expense of other regions of the brain that have suchprofound vasoconstriction to result in ischemic neurons.

Finally, current therapies to treat shock take time to work. Theseconventional therapies are frequently unable to optimize blood pressurein a timely fashion, and in many instances fail to achieve the intendedtarget altogether. For example, modern resuscitation is limited by thelatency period between an intervention and the recognition of thatintervention's physiologic effect, e.g., increase in blood pressure,urine output, oxygen saturation. Boluses of IV fluids require anywherefrom several minutes to an hour to be infused, and vasopressormedications often take 10-15 minutes to prepare, administer, and achievean effect large enough to be detected by a healthcare provider at thebedside, and often must be titrated in doses over the subsequent hours.Even once working, some forms of shock are not responsive to singlemedications and multiple vasopressors are required to optimize bloodpressure. As a result, valuable time is lost in the attempts to restorecardiovascular homeostasis and meet physiologic goals, e.g., targetblood pressure or markers of end organ perfusion, resulting in exceedingacceptable limits and irreversible tissue damage.

Furthermore, these end goals of resuscitation are frequently not evenachieved, despite maximal intervention with blood products, fluids, andmultiple vasoactive agents. This inherent delay is compounded by thefairly crude vital sign monitoring methods and metrics that haveundergone little change over the last 150 years. Therefore, conventionalresuscitation and monitoring strategies not only routinely fail toachieve goal hemodynamics in a timely fashion, but frequently fail toaccurately characterize and assess the adequacy of the treatmentaltogether. Since even short periods of ischemia can result in organdysfunction and decreased viability, leading to increased morbidity andmortality, improved strategies are needed to optimize blood flow andpressure in a more timely and reliable fashion.

The significant advancement of endovascular technologies to treatvascular pathology and injury over the past 25 years has provided aunique set of tools and techniques to facilitate a completely differentapproach to resuscitation in severe shock by directly optimizingcoronary, pulmonary and cerebral perfusion at the level of the aorta. Byusing endovascular catheters designed to impede distal blood flowstrategically placed within the aorta of a patient in shock, proximalblood pressure above the balloon can be augmented by minimizing bloodflow distal to the balloon. For example, Resuscitative EndovascularBalloon Occlusion of the Aorta (REBOA) is a therapy that is used intrauma patients in extremis. REBOA is an extreme version of afterloadaugmentation increasingly utilized by trauma providers in the setting ofuncontrolled torso hemorrhage. Rather than performing an emergencydepartment thoracotomy to cross clamp the aorta to minimize distalaortic flow, a balloon catheter is completely inflated in the aortaabove the level of injury to stop flow. By completely occluding theproximal aorta with balloon catheter, REBOA instantly isolates thedistribution of circulating blood to the upper torso, thereby improvingproximal organ perfusion and arresting bleeding downstream. Yet, thehemodynamic augmentation of REBOA does have a significantdrawback—ischemia to all tissue distal to the point of occlusion. Tocounter this drawback, a dynamic partial occlusion of the aorta, termedpartial-REBOA (P-REBOA) has been proposed as a method of supportingperfusion to vital organs (heart, lungs, brain) while still allowing fora low rate of distal blood flow. However, the clinical utility ofP-REBOA is currently limited by imprecise control of the degree ofocclusion.

Another type of occlusion device is the intra-aortic balloon pump usedfor patients in cardiogenic shock. Intra-aortic balloon pumps createpulsatile blood flow distally in the aorta to maximize coronarycirculation. A separate device termed the “neuro-flo” was brieflytrialed to improve perfusion to regions of the brain during a stroke bypartially occluding the aorta. However, “neuro-flo” lacks automation,and lacks an ability to change the amount of occlusion dynamically inresponse to patient physiology.

The current choices of endovascular compliant balloon architecture posestechnical challenges for carefully regulated distal aortic flow. As analternative to compliant balloon architectures, there existfixed-diameter, non-compliant balloon catheter designs (e.g., ARMADA® byAbbott Laboratories Corp., North Chicago, Ill.). However, thesecatheters are intended and approved for vessel dilation (angioplasty),typically for narrowed vessels (e.g., atherosclerosis). Additionally, afixed-diameter, non-compliant balloon catheter must be sizedappropriately to properly occlude each patient's aorta. Consequently,although the non-compliant balloon is less susceptible to change inshape due to blood pressure spikes, the inability to change diameteroutside of a narrow range impedes its ability to serve as an adaptabledevice to support both complete occlusion and partial occlusion.Therefore, the relatively fixed diameter of non-compliant ballooncatheters limits their real-world applicability across a range of normalaortic diameters.

Current balloon technology created for complete or partial aorticocclusion to stop distal hemorrhage in the setting of trauma are unableto provide consistent titrated flow across the complete range fromcomplete occlusion to no occlusion. The ER-REBOA catheter from PryTimeMedical is a compliant balloon catheter intended to decrease hemorrhageafter trauma. The ER-REBOA catheter and similar compliant balloons fromother manufacturers use balloons catheters that undergo conformationalchanges at varying degrees of occlusion resulting in non-predictablechanges in aortic flow with small changes in balloon cather volume.

Other efforts have been directed to development of potential alternativemethods of providing aortic occlusion. For example, Barbut et al., U.S.Pat. No. 6,743,196, issued Jun. 1, 2004, describes a plurality ofapproaches to support aortic occlusion. Each approach described inBarbut et al. includes a catheter having a distally mounted constrictingmechanism. Each constrictor is collapsed to facilitate insertion andthen expanded once inserted to obstruct blood flow. Barbut et al.describes a constrictor comprising an outer conical shell and an innerconical shell, each having a distal open base and proximal apex. Theouter shell further includes a pre-shaped ring to facilitate expansion.Both shells include ports or openings. Flow through the mechanism iscontrolled by rotating the inner conical shell such that the ports ofeach shell communicate.

More recently, VanCamp et al, in U.S. Pat. No. 7,927,346, issued Apr.19, 2011, describes a device to provide temporary partial aorticocclusion to achieve diversion of blood flow to the brain in patientssuffering from cerebral ischemia. The primary thrust of the VanCamp etal. invention is the provision of an blood flow regulation device thatdoes not require fluoroscopy to ensure proper placement. VanCamp'sdevice includes an expandable frame with a planar membrane mounted on afirst portion of the frame to occlude blood flow. In one embodimentdisclosed in VanCamp et al., the membrane includes a fixed size openingin the center of the planar membrane to allow some blood to flow throughthe opening. Alternatively, VanCamp also discloses that the membraneitself may be somewhat permeable to blood flow to allow some flow.However, VanCamp is unable to provide variable control of blood flowduring use.

In addition, Franklin et al, in PCT Pat. Appl. Pub. No. WO/2016149653A2,published Sep. 22, 2016, describes an occlusion catheter system andvascular pre-conditioning to mitigate ischemia before, during and/orafter a vascular occlusion procedure.

Medications including vasoactive medications and intravenous fluidsrequire time to improve physiology once physiologic derangement isrecognized. For example, vasoactive medications must circulatethroughout the vasculature and act through intracellular mechanisms toresult in vascular constriction. These changes can take seconds, tominutes, or even hours to take effect depending upon the medication usedand the underlying physiology. This time can be detrimental if the stateof shock is severe. The use of an endovascular device as described inthese claims allows for immediate augmentation of physiology onceinappropriate physiology is identified. Automation of an endovascularperfusion augmentation device allows this to be dynamic, with continuouschanges in the device on a second by second time frame to allowcontinuous stable physiology proximal to the device.

In light of the aforementioned considerations and limitations ofexisting and proposed devices, there exists an urgent and unmet need fora viable solution to allow a physician to address shock and carefullyregulate blood flow in the aorta to augment proximal blood pressure. Theability to rapidly deliver effective blood pressure and blood flow tothe heart, lungs and brain in shock states without using high amounts ofblood pressure medications and IV fluids will save innumerable lives.

SUMMARY

The present disclosure overcomes the drawbacks of previously describedsystems by providing an automated endovascular perfusion augmentationsystem. Recent translational experiments have demonstrated thatincorporating automation to precisely control partial aortic occlusionallows for distal aortic flow that can be finely titrated in response todynamic changes in blood pressure. While initially applied to settingsof ongoing hemorrhagic shock, it was posited that lesser degrees ofpartial aortic occlusion may optimize cardiac performance in any type ofshock by instant and dynamic changes in aortic afterload in a way thatIV fluids and medications cannot.

Endovascular Perfusion Augmentation for Critical Care (EPACC) directlyaddresses all of the above limitations of current therapies for shock inmany of its forms. Using automated devices to carefully control anendovascular aortic balloon catheter, EPACC provides small amounts ofblood pressure support to vascular beds above the balloon whilepermitting continued perfusion distal to the catheter balloon. Theconcept of EPACC, in contrast to techniques such as REBOA, works withonly partial occlusion of the aorta. REBOA maximizes proximal perfusionby completely occluding the aorta, at the expense of progressiveischemic injury to distal tissues. In contrast, EPACC only partiallyoccludes the aorta, resulting in a more physiologic augmentation ofproximal blood pressure. By placing the balloon at different levelswithin the aorta, the practitioner can select which distal capillarybeds are exposed to decreased flow. Deployment of EPACC in thedescending thoracic aorta results in mild reduction in blood flow to themesentery, kidneys, liver, and extremities. In contrast, deployment atthe aortic bifurcation only results in potential reduction in blood flowto the pelvis and limbs. Since aortic blood flow often exceeds what isphysiologically required, minimal to moderate aortic blood flowrestriction only results in minimal ischemia. This tradeoff betweenproximal blood pressure augmentation and distal ischemia is dependentupon the extent of shock as well as underlying patient's physiology.

The use of EPACC could be broad to treat a wide range of shock states.Initially EPACC was designed to treat shock following trauma,specifically the ischemia-reperfusion injury that is common followingREBOA and aortic cross clamping procedures. EPACC is just as viablethough for treating hemorrhagic shock when sufficient blood products arenot available, or septic shock to decrease the amount of IV fluids andvasopressors required for treatment. The ability of EPACC to beautomated to respond dynamically to any physiologic measure make it aviable technology to maximize cerebral perfusion in patients sufferingfrom traumatic brain injuries.

The system may include a catheter having a proximal end portion and adistal end portion, wherein the distal end portion may be placed withinan aorta of a patient. The system may further include an expandableaortic blood flow regulation device disposed on the distal end portionof the catheter for placement within the aorta. The expandable aorticblood flow regulation device may expand to restrict blood flow throughthe aorta and to contract. For example, the expandable aortic blood flowregulation device may be a balloon that may be inflated to expand topartially occlude blood flow through the aorta. In another embodiment,the expandable aortic blood flow regulation device may include a balloonthat may be inflated to occlude blood flow through the aorta, and one ormore wires that surround the balloon. Accordingly, the one or more wiresmay be tightened to indent the balloon to permit blood flow around theballoon. In another embodiment, the expandable aortic blood flowregulation device may include a wire framework that may radially expandor contract from a center axis of the catheter, and an blood flowregulation sail comprising a thin membrane that surrounds a portion ofthe wire framework. In another embodiment, the expandable aortic bloodflow regulation device may include a non-compliant balloon having one ormore windows, and a compliant balloon enclosed within the non-compliantballoon.

In one embodiment, the system may further comprise a second expandableaortic blood flow regulation device disposed on the distal end portionof the catheter proximal to the expandable aortic blood flow regulationdevice for placement within the aorta. The second expandable aorticblood flow regulation device may be coupled to the catheter controllerunit and may expand to partially occlude blood flow through the aortaand to contract. The expandable aortic blood flow regulation device andthe second expandable aortic blood flow regulation device may be spacedapart such that the expandable aortic blood flow regulation device isplaced in a zone of the aorta, and the second expandable aortic bloodflow regulation device is placed in a different zone of the aorta.

The system may further include a catheter controller unit coupled to theproximal end portion of the catheter. The catheter controller unit maycause the expandable aortic blood flow regulation device to expand andcontract in the aorta. When the expandable aortic blood flow regulationdevice is a balloon that may be inflated to expand to partially occludeblood flow through the aorta, e.g., a balloon catheter, the cathetercontroller unit may include a syringe pump that may inflate or deflatethe balloon to adjust the amount of blood flow through the aorta if themeasured physiological information falls outside the targetphysiological range. When the expandable aortic blood flow regulationdevice is a balloon having one or more wires surrounding the balloon,e.g., a wire-over-balloon catheter, the catheter controller unit mayinclude a syringe pump that may inflate or deflate the balloon, and astepper motor or a motorized arm that may shorten or lengthen the one ormore wires to tighten or loosen the one or more wires surrounding theballoon to adjust the amount of blood flow through the aorta if themeasured physiological information falls outside the targetphysiological range. When the expandable aortic blood flow regulationdevice is a wire framework having an blood flow regulation sail, e.g.,an intra-aortic sail catheter, the catheter controller unit may includea stepper motor or a motorized arm that may shorten or lengthen the wireframework to radially expand or contract the blood flow regulation sailto adjust the amount of blood flow through the aorta if the measuredphysiological information falls outside the target physiological range.When the expandable aortic blood flow regulation device is a compliantballoon enclosed within a non-compliant balloon, the catheter controllerunit may be a syringe pump that may inflate or deflate the compliantballoon such that the compliant balloon is extruded through the one ormore windows of the non-compliant balloon to adjust the amount of bloodflow through the aorta if the measured physiological information fallsoutside the target physiological range.

The system may further include one or more sensors for measuringphysiological information indicative of blood flow through the aorta.For example, one of the one or more sensors may be disposed on thecatheter distal to the expandable aortic blood flow regulation deviceand may measure physiological information indicative of blood pressurein the aorta distal to the expandable aortic blood flow regulationdevice, and/or one of the one or more sensors may be disposed on thecatheter proximal to the expandable aortic blood flow regulation deviceand may measure physiological information indicative of blood pressurein the aorta proximal to the expandable aortic blood flow regulationdevice. The one or more sensors may measure physiological informationindicative of blood flow through the aorta including at least one ofheart rate, respiratory rate, aortic blood flow proximal or distal tothe expandable aortic blood flow regulation device, blood temperature,pressure within the expandable aortic blood flow regulation device,cardiac output of the patient, carotid blood flow, pulmonary pressures,peripheral vascular resistance, or intracranial pressure. Additionally,the one or more sensors may measure physiological information indicativeof blood flow through the aorta by measuring at least one of lactatelevel, cortisol level, reactive oxygen species level, or pH, of a fluidof the patient. In an embodiment where two expandable aortic blood flowregulation devices are utilized, at least one of the one or more sensorsmay be positioned distal to the expandable aortic blood flow regulationdevice, in between the expandable aortic blood flow regulation deviceand the second expandable aortic blood flow regulation device, orproximal to the second expandable aortic blood flow regulation device.

The system may further include a non-transitory computer readable mediahaving instructions stored thereon, wherein the instructions, whenexecuted by a processor coupled to the one or more sensors, cause theprocessor to compare the measured physiological information with atarget physiological range such that the catheter controller unitautomatically adjusts expansion and contraction of the expandable aorticblood flow regulation device to adjust an amount of blood flow throughthe aorta if the measured physiological information falls outside thetarget physiological range.

In one embodiment, the system may further comprise an external centralprocessing unit operatively coupled to the one or more sensors and thecatheter controller unit. The external central processing unit mayinclude the processor and transmit information indicative of whether themeasured physiological information falls outside the targetphysiological range to the catheter controller unit. For example, theexternal central processing unit may transmit the information to thecatheter controller unit via at least one of WiFi, Bluetooth,Wixel-based communication, or cellular communication.

In one embodiment, the system may further comprise an automated pump fordelivering intravenous medication to the patient, wherein theinstructions, when executed by the processor coupled to the one or moresensors, cause the processor to compare the measured physiologicalinformation with a target physiological range such that the automatedpump delivers intravenous medications to the patient to modulate patientphysiology based on the comparison.

In one embodiment, the system may further comprise an automated pump fordelivering intravenous fluids and blood products to the patient, whereinthe instructions, when executed by the processor coupled to the one ormore sensors, cause the processor to compare the measured physiologicalinformation with a target physiological range such that the automatedpump delivers intravenous fluids or blood products to the patient tomodulate patient physiology based on the comparison.

In accordance with yet another aspect of the present disclosure, amethod for automatically, dynamically regulating the degree of aorticblood flow regulation for endovascular perfusion augmentation. Themethod may include introducing a distal end portion of a catheter havingan expandable aortic blood flow regulation device within an aorta of apatient, expanding the expandable aortic blood flow regulation device topartially occlude blood flow through the aorta, measuring physiologicalinformation indicative of blood flow through the aorta via one or moresensors, comparing the measured physiological information with a targetphysiological range, and adjusting expansion and contraction of theexpandable aortic blood flow regulation device to adjust an amount ofblood flow through the aorta if the measured physiological informationfalls outside the target physiological range.

In one embodiment, the catheter further includes a second expandableaortic blood flow regulation device disposed on the distal end portionof the catheter proximal to the expandable aortic blood flow regulationdevice for placement within an aorta or distal artery of a patient. Thesecond expandable aortic blood flow regulation device may expand topartially occlude blood flow, and the expandable aortic blood flowregulation device may be placed in a zone of the aorta, while the secondexpandable aortic blood flow regulation device may be placed in adifferent zone of the aorta or in blood vessels more distal to theaorta. Accordingly, the method may further include expanding the secondexpandable aortic blood flow regulation device to occlude blood flow,and expanding or contracting the second expandable aortic blood flowregulation device to adjust the amount of blood flow if the measuredphysiological information falls outside the target physiological range.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates an exemplary automated endovascular perfusionaugmentation system constructed in accordance with the principles of thepresent disclosure.

FIG. 2A illustrates a balloon catheter constructed in accordance withthe principles of the present disclosure. FIG. 2B shows the ballooncatheter of FIG. 2A placed in series within an aorta of a patient.

FIG. 3A illustrates a wire-over-balloon catheter having two wires. FIG.3B illustrates the wire-over-balloon catheter of FIG. 3A wherein thewires are tightened to indent the balloon.

FIG. 4A illustrates a wire-over-balloon catheter having three wires.FIG. 4B illustrates the wire-over-balloon catheter of FIG. 4A whereinthe wires are tightened to indent the balloon. FIG. 4C shows thewire-over-balloon catheter of FIG. 4B placed in series within an aortaof a patient.

FIG. 5A illustrates an intra-aortic sail catheter constructed inaccordance with the principles of the present disclosure. FIG. 5B showsthe intra-aortic sail catheter of FIG. 5A placed in series within anaorta of a patient.

FIG. 6 illustrates a caged-balloon catheter constructed in accordancewith the principles of the present disclosure.

FIG. 7 is a schematic of an exemplary catheter controller unitconstructed in accordance with the principles of the present disclosure.

FIG. 8 is a schematic of an exemplary external central processing unitconstructed in accordance with the principles of the present disclosure.

FIG. 9 is a flow chart illustrating an exemplary method forautomatically, dynamically regulating the degree of aortic blood flowregulation for endovascular perfusion augmentation in accordance withthe principles of the present disclosure.

FIG. 10 is a flow chart illustrating a study comparing EPACC andStandard Critical Care.

FIG. 11 illustrates charts depicting hemodynamic data derived from thestudy comparing EPACC and Standard Critical Care.

FIG. 12 illustrates charts depicting primary outcomes of interestderived from the study comparing EPACC and Standard Critical Care.

FIG. 13 illustrates charts depicting secondary outcomes of interestderived from the study comparing EPACC and Standard Critical Care.

DETAILED DESCRIPTION

Endovascular Perfusion Augmentation for Critical Care (EPACC) is a noveltherapeutic platform to mechanically and pharmacologically augment bloodpressure of patients with critical illness. EPACC is achieved via asystem comprising a series of endovascular devices, controller units forthose devices, and complex algorithms capable of real-time changes inthe EPACC devices in response to patient physiology. The ability ofEPACC to be automated to respond dynamically to any physiologic measuremakes it a viable technology to maximize perfusion in multiple shockstates. In accordance with the principles of the present disclosure,EPACC is just as viable though for treating hemorrhagic shock whensufficient blood products are not available, or septic shock to decreasethe amount of IV fluids and vasopressors required for treatment, orneurogenic shock in the setting of traumatic brain injury orintracerebral hemorrhage.

Referring to FIG. 1, an exemplary automated endovascular perfusionaugmentation system constructed in accordance with the principles of thepresent disclosure is described. In FIG. 1, the components of automatedendovascular perfusion augmentation system 100 are not depicted to scaleon either a relative or absolute basis. System 100 comprises catheter102 coupled to catheter controller unit 700 and external processing unit800 (optional). Catheter 102 includes distal end 103 and proximal end105, and is sized and shaped for placement within aorta A of patient P.Catheter 102 may be any catheter well-known in the art, having a lengthsufficiently long such that catheter 102 may be inserted into a patientvia the femoral artery or radial artery, and extend through thepatient's vasculature into the aorta. Catheter 102 may also includeexpandable blood flow regulation device 104 and sensors 106 disposed atdistal end 103.

Unlike current intra-aortic catheters, catheter 102 may be designed tobe used for EPACC. For example, expandable blood flow regulation device104 of catheter 102 may be designed to expand and contract, e.g.,inflate and deflate, without undergoing morphological changes over time.

Expandable blood flow regulation device 104 may be strategically placedwithin the aorta of a patient in shock and is designed to regulate bloodflow through the aorta of the patient such that blood flow distal toexpandable blood flow regulation device 104 may be impeded to augmentblood pressure proximal to expandable blood flow regulation device 104.Expandable blood flow regulation device 104 may comprise two expandableblood flow regulation devices disposed in series at distal end 103 ofcatheter 102. Accordingly, the expandable blood flow regulation devicesmay be spaced apart such that one expandable blood flow regulationdevice is placed in a specified zone of the aorta, and the secondexpandable blood flow regulation device is placed in a differentspecified zone of the aorta. For example, one expandable blood flowregulation device may be placed in zone 1 of the aorta, while the secondexpandable blood flow regulation device is placed in zone 3 of theaorta. As such, by placing the expandable blood flow regulation devicesat different levels within the aorta, the practitioner may select whichdistal capillary beds are exposed to decreased flow. For example,placing and expanding an expandable blood flow regulation device in zone1 of the aorta results in mild reduction in blood flow to the mesentery,kidneys, liver, and extremities of the patient. In contrast, placing andexpanding an expandable blood flow regulation device results inpotential reduction in blood flow to the pelvis and limbs of thepatient. Expandable blood flow regulation device 104 may comprisevarious balloons and/or alternative device designs as described infurther detail below.

As expandable blood flow regulation device 104 only partially restrictsblood flow in the aorta, more physiologic augmentation of proximal bloodpressure may result, while simultaneously optimizing blood flow todownstream organs and tissue beds. Since aortic blood flow is greateroverall than is physiologically required in the majority of cases forpatient's in shock, minimal-to-moderate occlusion results in onlyminimal ischemia. This tradeoff between proximal blood pressureaugmentation and distal ischemia is dependent upon the extent of shockas well as the patient's underlying physiology.

Sensors 106 may measure physiological information indicative of bloodflow through the aorta to determine the patient's underlying physiology.For example, sensors 106 may measure physiological parameters including,but not limited to, heart rate, respiratory rate, blood pressureproximal or distal or in between the two expandable blood flowregulation devices, aortic blood flow proximal or distal or in betweenthe two expandable blood flow regulation devices, blood temperature,pressure within the expandable blood flow regulation device, cardiacoutput of the patient, carotid blood flow, pulmonary pressures,peripheral vascular resistance, or intracranial pressure. Sensors 106may include one or more sensors. For example, as shown in FIG. 1,sensors 106 comprise three sensors, and may be positioned along catheter102 distal to the expandable blood flow regulation device, in betweenthe expandable blood flow regulation device and the second expandableblood flow regulation device, and/or proximal to the second expandableblood flow regulation device.

Sensors 106 may record data indicative of the measured physiologicalinformation either through analog or digital mechanisms. This data maythen be used to determine whether more or less restriction of aorticblood flow is required to maximize vital organ perfusion via automatedaugmentation of blood pressure, as described in further detail below.

Patient physiology may also be monitored via real-time and intermittentmeasures of compounds with in the patient's blood, serum, urine, orsaliva, e.g., levels of lactate, levels of cortisol, levels of reactiveoxygen species, the pH of the fluid, as well as other commonly usedpatient physiology markers.

Catheter controller unit 700 may be coupled to proximal end 105 ofcatheter 102. Catheter controller unit 700 may receive the dataindicative of the measured physiological information from sensors 106,and determine whether the measured physiological information is within apredetermined target physiological range. Catheter controller unit 700may also be coupled to expandable blood flow regulation device 104 suchthat catheter controller unit 700 automatically adjusts expansion andcontraction of expandable blood flow regulation device 104 to adjust theamount of blood flow through the aorta if the measured physiologicalinformation falls outside the target physiological range as described infurther detail below.

In one embodiment, system 100 includes external central processing unit800. External central processing unit 800 may be operatively coupled tosensors 106 and catheter controller unit 700 such that external centralprocessing unit 800 may receive the data indicative of the measuredphysiological information from sensors 106, determine whether themeasured physiological information is within a predetermined targetphysiological range, calculate the amount of change of size ofexpandable blood flow regulation device 104 to bring the patientphysiology within the target physiological range, and transmitinformation indicative of whether the measured physiological informationfalls outside the target physiological range to central processing unit800 as described in further detail below. Accordingly, cathetercontroller unit 700 automatically adjusts expansion and contraction ofexpandable blood flow regulation device 104 to adjust the amount ofblood flow through the aorta based on the information received fromexternal central processing unit 800.

Referring to FIG. 2A, a balloon catheter constructed in accordance withthe principles of the present disclosure is described. As shown in FIG.2A, expandable blood flow regulation device 104 of FIG. 1 may compriseballoon catheter 200. Balloon catheter 200 comprises balloon 204positioned at the distal end of catheter 102. Balloon 204 is designed tobe inflated to a carefully titrated balloon volume to regulate bloodflow in the aorta. For example, an incompressible fluid may beintroduced into balloon 204 through a lumen of catheter 102 via exitports 202 such that balloon 204 may maintain the carefully titratedballoon volume. Balloon 204 may be made of a suitable membrane that willprevent diffusion of the inflation fluid across the membrane and intothe vasculature of the patient. The membrane may also be designed toinflate and deflate without undergoing morphological changes over time.

As shown in FIG. 2B, balloon catheter 200 may be placed within aorta Aof the patient in series with additional balloon catheter 210. Ballooncatheter 210 may be constructed similarly to balloon catheter 200.Balloon catheter 200 and balloon catheter 210 may be individuallyinflated and deflated such that each balloon catheter maintains its ownallocated carefully titrated balloon volume. Balloon catheter 200 andballoon catheter 210 may be spaced apart along the distal end ofcatheter 102 such that balloon catheter 200 is placed within, e.g., zone1 of the aorta, and balloon catheter 210 is placed within, e.g., zone 3of the aorta. This allows for blood pressure to be regulated aboveballoon catheter 200 in zone 1 and simultaneously above balloon catheter210 in zone 2. As such, catheter 102 may selectively normalize perfusionto critical organs while allowing regionalized hypoperfusion to lesscritical organs and extremities for defined time periods. As shown inFIG. 2B, sensors 106 may comprise three sensors, e.g., solid-statepressure sensors or pressure monitoring ports, positioned above ballooncatheter 200 and above and below balloon catheter 210 to allow pressuremonitoring in all three zones of the aorta. As will be understood by oneskilled in the art, a single balloon catheter or more than two ballooncatheters may be placed within the aorta for EPACC.

Referring now to FIGS. 3A and 3B, an exemplary wire-over-ballooncatheter is described. As shown in 3A and 3B, expandable blood flowregulation device 104 of FIG. 1 may comprise wire-over-balloon catheter300. Wire-over-balloon catheter 300 comprises balloon 304 positioned atthe distal end of catheter 102, and two wires 306 externally surroundingballoon 304. As shown in FIG. 3A, balloon 304 is designed to be inflatedto fully occlude the aorta. For example, an incompressible fluid may beintroduced into balloon 304 through a lumen of catheter 102 via exitports 302 such that balloon 304 may maintain the inflated balloonvolume. Balloon 304 may be made of a suitable membrane that will preventdiffusion of the inflation fluid across the membrane and into thevasculature of the patient. The membrane may also be designed to inflateand deflate without undergoing morphological changes over time.

Wires 306 may be fixed to a point along catheter 102 distal to balloon304, traverse over balloon 304 along the longitudinal axis of balloon304, and extend through a lumen of catheter 102 to a fixed pointproximal to balloon 304. As such, catheter 102 may comprise separatelumens for receiving wires 306 and for inflating balloon 304 asdescribed above. Wires 306 may surround balloon 304 such that wires 306contact the wall of the aorta when balloon 304 is fully inflated. Asshown in FIG. 3B, wires 306 may be immediately tightened to indentballoon 304 and create a gap between the wall of the aorta and the outersurface of balloon 304, such that the tension of wires 306 and thedegree of deformation of balloon 304 correspond with the amount of bloodflow past the balloon within the aorta. The degree of deformation ofballoon 304 may also depend on the size of wires 306, e.g., a largerwire will result in a larger indentation.

Referring now to FIGS. 4A and 4B, another exemplary wire-over-ballooncatheter is described. As shown in FIGS. 4A and 4B, expandable bloodflow regulation device 104 of FIG. 1 may comprise wire-over-ballooncatheter 400. Wire-over-balloon catheter 400 is constructed similarly towire-over-balloon catheter 300 of FIGS. 3A and 3B. For example,wire-over-balloon catheter 400 comprises balloon 404 positioned at thedistal end of catheter 102, and may be inflated with an incompressiblefluid via exit ports 402 of catheter 102 to fully occlude the aorta.However, wire-over-balloon catheter 400 comprises three wires 406externally surrounding balloon 404. As shown in FIG. 4B, wires 406 maybe immediately tightened to indent balloon 404 and create a gap betweenthe wall of the aorta and the outer surface of balloon 404, such thatthe tension of wires 406 and the degree of deformation of balloon 404correspond with the amount of blood flow past the balloon within theaorta. As will be understood by one of ordinary skill in the art, asingle wire or more than three wires may be used in a wire-over-ballooncatheter. Further, the wires may surround the balloon in a manner otherthan along the longitudinal axis of the balloon such that the wiresindent the balloon to permit blood flow past the balloon based on thedegree of indentation of the balloon by the wires.

As shown in FIG. 4C, wire-over-balloon catheter 400 may be placed withinaorta A of the patient in series with additional wire-over-ballooncatheter 410. Wire-over-balloon catheter 410 may be constructedsimilarly to wire-over-balloon catheter 400. The wires ofwire-over-balloon catheter 400 and wire-over-balloon catheter 410 may beindividually tightened and loosened such that each wire-over-ballooncatheter maintains its own carefully allocated degree of indentation.Wire-over-balloon catheter 400 and wire-over-balloon catheter 410 may bespaced apart along the distal end of catheter 102 such thatwire-over-balloon catheter 400 is placed within, e.g., zone 1 of theaorta, and wire-over-balloon catheter 410 is placed within, e.g., zone 3of the aorta. This allows for blood pressure to be regulated abovewire-over-balloon catheter 400 in zone 1 and simultaneously abovewire-over-balloon catheter 410 in zone 2. As such, catheter 102 mayselectively normalize perfusion to critical organs while allowingregionalized hypoperfusion to less critical organs and extremities fordefined time periods. As shown in FIG. 4C, sensors 106 may comprisethree sensors, e.g., solid-state pressure sensors or pressure monitoringports, positioned above wire-over-balloon catheter 400 and above andbelow wire-over-balloon catheter 410 to allow pressure monitoring in allthree zones of the aorta. As will be understood by one skilled in theart, a single wire-over-balloon catheter or more than twowire-over-balloon catheters may be placed within the aorta for EPACC.

Referring now to FIG. 5A, an intra-aortic sail catheter constructed inaccordance with the principles of the present disclosure is described.As shown in FIG. 5A, expandable blood flow regulation device 104 of FIG.1 may comprise intra-aortic sail catheter 500. Intra-aortic sailcatheter 500 may be constructed as disclosed by Williams et al., U.S.Patent Application Publication No. 2016/0206798, published Jul. 21,2016, which is incorporated by reference herein in its entirety. Forexample, intra-aortic sail catheter 500 comprises wire framework 502 andthin membrane 504 positioned at the distal end of catheter 102, whereinmembrane 504 surrounds a portion of wire framework 502. Wire framework502 comprises a plurality of wires that may be fixed to a point alongcatheter 102 distal to membrane 504, and extend through a lumen ofcatheter 102 to a fixed point proximal to membrane 504. The portion ofthe wires of wire framework 502 that is surrounded by membrane 502 mayexpand radially from the longitudinal axis of intra-aortic sail catheter500. The wires of wire framework 502 may be expand radially such thatthe wires are equally spaced apart circumferentially in the expandedposition. Accordingly, as wire framework 502 expands radially, membrane504 expands creating a sail within the aorta, such that the tension ofwire framework 502 and the degree of expansion of membrane 504correspond with the amount of blood flow past the intra-aortic sailwithin the aorta.

As shown in FIG. 5B, intra-aortic sail catheter 500 may be placed withinaorta A of the patient in series with additional intra-aortic sailcatheter 510. Intra-aortic sail catheter 510 may be constructedsimilarly to intra-aortic sail catheter 500. The wire frameworks ofintra-aortic sail catheter 500 and intra-aortic sail catheter 510 may beindividually tightened and loosened such that each intra-aortic sailcatheter maintains its own carefully allocated degree of aorticocclusion. Intra-aortic sail catheter 500 and intra-aortic sail catheter510 may be spaced apart along the distal end of catheter 102 such thatintra-aortic sail catheter 500 is placed within, e.g., zone 1 of theaorta, and intra-aortic sail catheter 510 is placed within, e.g., zone 3of the aorta. This allows for blood pressure to be regulated aboveintra-aortic sail catheter 500 in zone 1 and simultaneously aboveintra-aortic sail catheter 510 in zone 2. As such, catheter 102 mayselectively normalize perfusion to critical organs while allowingregionalized hypoperfusion to less critical organs and extremities fordefined time periods. As shown in FIG. 5B, sensors 106 may comprisethree sensors, e.g., solid-state pressure sensors or pressure monitoringports, positioned above intra-aortic sail catheter 500 and above andbelow intra-aortic sail catheter 510 to allow pressure monitoring in allthree zones of the aorta. As will be understood by one skilled in theart, a single intra-aortic sail catheter or more than two intra-aorticsail catheters may be placed within the aorta for EPACC.

Referring now to FIG. 6, a caged-balloon catheter constructed inaccordance with the principles of the present disclosure is described.As shown in FIG. 6, expandable blood flow regulation device 104 of FIG.1 may comprise caged-balloon catheter 600. Caged-balloon catheter 600comprises non-compliant outer balloon 602 positioned at the distal endof catheter 102, and compliant inner balloon 606 enclosed withinnon-compliant outer balloon 602. Non-compliant outer balloon 602includes one or more windows 604 sized to permit compliant inner balloon606 to extrude therethrough when compliant inner balloon 606 isinflated. The number of windows correspond to the number of extrusionsof compliant inner balloon 606 through non-compliant outer balloon 602.The shape of windows 604 controls the shape of compliant inner balloon606 during partial inflation. Compliant balloon 606 is designed to beinflated to a carefully titrated balloon volume to regulate blood flowin the aorta. At full inflation, compliant inner balloon 606 maycompletely occlude the aorta. For example, an incompressible fluid maybe introduced into compliant inner balloon 606 through a lumen ofcatheter 102 such that compliant inner balloon 606 may maintain thecarefully titrated balloon volume. Compliant inner balloon 606 may bemade of a suitable membrane that will prevent diffusion of the inflationfluid across the membrane and into the vasculature of the patient. Themembrane may also be designed to inflate and deflate without undergoingmorphological changes over time. As described above, caged-ballooncatheter 600 may be placed within aorta A of the patient in series withadditional caged-balloon catheter. The compliant inner balloons of eachcaged-balloon catheter may be individually inflated and deflated suchthat each caged-balloon catheter maintains its own carefully allocatedcarefully titrated balloon volume. The caged-balloon catheters may alsobe spaced apart along the distal end of catheter 102 such that thecaged-balloon catheters are placed within different levels of the aorta.Any combination of the expandable blood flow regulation deviceembodiments described above may be used in series as will be understoodby one skilled in the art.

Referring to FIG. 7, an exemplary catheter controller unit constructedin accordance with the principles of the present disclosure isdescribed. As shown in FIG. 7, catheter controller unit 700 comprisesprocessor 702 having memory 704 and communication circuitry 706, anddrive mechanism 708. In FIG. 7, components of processor 702 are notdepicted to scale on either a relative or absolute basis. Processor 702may be operatively coupled to sensors 106 and drive mechanism 708, anddrive mechanism 708 may be operatively coupled to expandable blood flowregulation device 104.

Processor 702 may receive data indicative of the measured physiologicalinformation from sensors 106 via communication circuitry 706. Memory704, non-transitory computer readable media, may store a targetphysiological parameter and a corresponding range associated with bloodflow through the aorta, and instructions that, when executed byprocessor 702, cause processor 702 to compare the measured physiologicalinformation with the target physiological range to determine whether themeasured physiological information is within the predetermined targetphysiological range. As such, processor 702 may calculate an appropriatechange in the amount of occlusion by expandable blood flow regulationdevice 104 necessary to bring the patient physiology within the targetphysiological range based on the current measured patient physiology.

Processor 702 comprises a series of sub-algorithms for controlling eachaspect of appropriate balloon inflation, deflation, and rate of responseto physiologic changes when a balloon-based catheter is used, e.g.,balloon catheter 200, wire-over-balloon catheter 300, 400, orcaged-balloon catheter 600, or when a wire-based catheter is used, e.g.,wire-over-balloon catheter 300, 400 or intra-aortic sail catheter 500,the deployment, retraction and rate of change of the wire-basedcatheter. These individual algorithms may also calculate: initialcalibration to identify the physical measurements of the vessel,determination of complete occlusion, identification of a working rangeof the catheter, e.g., the range of occlusion that results due tochanges in patient physiology, set point optimization, weaning off fromcatheter-based physiologic support, and balloon volume tuning.

For balloon catheter 200, the balloon calibration sequence occurs uponinitial insertion of the catheter or upon initiation of EPACC. Thecalibration sequence is also activated any time large changes in thehemodynamics are detected that are not induced by EPACC. Upon initiationof the balloon calibration sequence, drive mechanism 708 of cathetercontroller unit 700 will iteratively introduce small aliquots of gas orfluid, e.g., carbon dioxide, saline, or a mixture of contrast andsaline, into the balloon. During sequential boluses, proximal physiologymay be monitored until a change is observed, which denotes the low setpoint of the working range of balloon 204. Balloon 204 will continue toinflate until the distal blood pressure waveform is extinguished oruntil proximal physiologic changes are no longer observed, which denotesthe upper working range of balloon catheter 200. Alternatively, theupper limit may be denoted by measuring the cessation of aortic flow. Amid-point of the working range may be set as an interval increase inballoon volume from the low set point and may be referenced for a rapidreturn to working range if needed during EPACC.

For wire-over-balloon catheters 300, 400 a similar calibration sequencemay be followed. Initial low and high balloon set points are determinedwith iterative inflation of the balloon of the wire-over-ballooncatheter while monitoring proximal physiology. After complete occlusionor when maximal inflation is achieved, the wires are immediatelyactivated to allow for blood flow past the balloon. During wireactivation, proximal and distal physiology may be monitored such thatthe degree of wire activation is noted when physiology is observed to nolonger change. This set point denotes the low range of wire activation,with no wire activation denoted as the high range for wire activation.

For intra-aortic sail catheter 500, the calibration sequence is similarto the balloon catheter sequence except that the low and high points forset points are denoted based solely off of proximal physiologic changes,e.g., the point that proximal physiology begins to change and the pointwhen no further change is observed.

After balloon calibration has occurred and initial balloon volume setpoints have been identified, processor 702 causes catheter controllerunit 700 to adjust the shape and size of expandable blood flowregulation device 104 via drive mechanism 708 to augment proximal bloodpressure responsive to patient physiology. As described above, processor702 compares the measured physiological information received fromsensors 106 with the target physiological range stored in memory 704 todetermine whether the measured physiological information is within thepredetermined target physiological range. For example, if proximal bloodpressure is set as the physiologic marker, when processor 702 determinesthat proximal blood pressure drops below the target blood pressurerange, catheter controller unit 700 expands expandable blood flowregulation device 104 via drive mechanism 708, e.g., inflate theballoon, decrease the wire tension in a wire-over-balloon catheterdesign, or expand the wire framework in an aortic sail design.Similarly, when processor 702 determines that proximal blood pressureexceeds the target blood pressure range, catheter controller unit 700contracts expandable blood flow regulation device 104 via drivemechanism 708, e.g., deflate the balloon, increase the wire tension in awire-over-balloon catheter design, or contract the tension of the wireframework in an aortic sail design. The amount of change in balloonvolume or wire tension that occurs in response to blood pressure changesthat are out of range is dependent upon how far the current measuredblood pressure is from the target blood pressure. Therefore, if theblood pressure is only minimally out of the target range, a small changein size of expandable blood flow regulation device 104 is made. Incontrast, when the blood pressure is significantly out of the targetrange, a larger change in size of expandable blood flow regulationdevice 104 is made. An example algorithm that may be used to provideEPACC includes:

uLBolus=(P ₀ −P _(s))² *V

where P₀ is current pressure, P_(s) is set point pressure, and V is aconstant described below. One skilled in the art will understand thatalternative algorithms could be used to adjust balloon volumes basedupon current and goal physiology.

The balloon tuning, wire tuning, or sail tuning algorithm allows for themagnitude of the change of size of expandable blood flow regulationdevice 104 in response to the difference between the measuredphysiological information and the target physiological parameter to bedynamic, controlled by the constant V. Initially V may be set to adefault, but V may change dynamically dependent upon the magnitude ofphysiologic changes that occur beyond the initial target set points. Forexample, if blood pressure is set as the physiologic marker and theinitial blood pressure recorded by sensors 106 was below the set pointpressure, but the resulting blood pressure recorded by sensors 106 afterthe change in expansion amount of expandable blood flow regulationdevice 104 by drive mechanism 708 is above the set point pressure, Vwould then be modified in order to correct for overshooting the goal setpoint. If the measured blood pressure is determined to be within thetarget blood pressure and as a result, the amount of expansion ofexpandable blood flow regulation device 104 drops below the low setpoint, expandable blood flow regulation device 104 will then wean off toits baseline zero set point. This may occur by either deflating theballoon, further indenting the balloon, or by retracting theintra-aortic sail.

As described above, processor 702 may automatically expand and contractexpandable blood flow regulation device 104 via drive mechanism 708 inaccordance with the principles of the present disclosure. For example,when expandable blood flow regulation device 104 comprises ballooncatheter 200 or caged-balloon catheter 600, drive mechanism 708 may be asyringe pump designed to inject or remove fluid from the balloon toinflate or deflate the balloon via the exit ports in fluid communicationwith the lumen of catheter 102. The syringe pump may make small titratedchanges in balloon volume in response to patient physiology viaautomation.

As described above, the balloon catheters may be placed in series withinthe aorta and may be individually inflated and deflated such that eachballoon catheter maintains its own allocated carefully titrated balloonvolume. As such, the syringe pump of drive mechanism 708 may beoperatively coupled to the balloons via multiple lumens extendingthrough catheter 102. For example, one lumen may permit the syringe pumpto inject or remove fluid from the balloon placed in zone 1 of theaorta, while another lumen may permit syringe pump to inject or removefluid from the balloon placed in zone 3 of the aorta. As such, bloodpressure may be regulated in different levels of the aorta.

When expandable blood flow regulation device 104 compriseswire-over-balloon catheter 300, 400, drive mechanism 708 may comprise asyringe pump designed to insert or remove fluid from the balloon toinflate or deflate the balloon via the exit ports in fluid communicationwith the lumen of catheter 102 as described above, and a controller armdesigned to manipulate the wires that overlie the balloon to tighten orloosen the wire against the balloon, allowing for careful titratedchanges in balloon indentation in response to patient physiology viaautomation. For example, the controller arm of drive mechanism 708 mayinclude a stepper motor that may shorten or lengthen the wires relativeto a fixed point at the proximal end of catheter 102, or a motorized armthat may tighten or loosen the wires to change the tension of the wiresrelative to a fixed point at the proximal end of catheter 102. Oneskilled in the art will realize that alternative methods for changingthe length of the wire over the balloon could be used.

As described above, the wire-over-balloon catheters may be placed inseries within the aorta and may be individually indented such that eachwire-over-balloon catheter maintains its own allocated carefullyallocated degree of indentation. As such, the syringe pump of drivemechanism 708 may be operatively coupled to the balloons via multiplelumens extending through catheter 102. For example, one lumen may permitthe syringe pump to inject or remove fluid from the balloon placed inzone 1 of the aorta, while another lumen may permit syringe pump toinject or remove fluid from the balloon placed in zone 3 of the aorta.Similarly, the controller arm of drive mechanism 708 may be operativelycoupled to the wires of each wire-over-balloon catheter via multiplelumens extending through catheter 102 such that one lumen may permit thecontroller arm to tighten or loosen the wires of the wire-over-ballooncatheter placed in zone 1 of the aorta, while another lumen may permitthe controller arm to tighten or loosen the wires of thewire-over-balloon catheter placed in zone 3 of the aorta. As such, bloodpressure may be regulated in different levels of the aorta.

When expandable blood flow regulation device 104 comprises intra-aorticsail catheter 500, drive mechanism 708 may comprise a controller armdesigned to manipulate wire framework 502 in response to patientphysiology via automation. As described above, the controller arm ofdrive mechanism 708 may include a stepper motor that may shorten orlengthen the wires of wire framework 502 relative to a fixed point atthe proximal end of catheter 102, or a motorized arm that may tighten orloosen the wires to change the tension of the wires of wire framework502 relative to a fixed point at the proximal end of catheter 102.

As described above, the intra-aortic sail catheters may be placed inseries within the aorta and may be individually expanded such that eachintra-aortic sail catheter maintains its own carefully allocated degreeof expansion. As such, the controller arm of drive mechanism 708 may beoperatively coupled to the wire framework of each intra-aortic sailcatheter via multiple lumens extending through catheter 102. Forexample, one lumen may permit the controller arm to tighten or loosenthe wire framework of the intra-aortic sail catheter placed in zone 1 ofthe aorta, while another lumen may permit the controller arm to tightenor loosen the wire framework of the intra-aortic sail catheter placed inzone 3 of the aorta. As such, blood pressure may be regulated indifferent levels of the aorta. As described above, any combination ofthe aforementioned expandable blood flow regulation device embodimentsmay be used in series as will be understood by one skilled in the art.Accordingly, drive mechanism 708 may comprise any combination of thesyringe pump and controller arms to provide unique expansion and controlof the individual expandable blood flow regulation devices.

After each change in balloon volume or wire tension by drive mechanism708 of catheter controller unit 700, processor 702 may wait for apredetermined period of time for the resulting physiologic response tobe monitored before further adjusting the balloon volume or wiretension.

In one embodiment, drive mechanism 708 may provide for manual inflationof the balloon or manual tightening of the wires, e.g., when automationis either unavailable or not feasible. For example, a manual drivemechanism may include a syringe pump that may inject fluid using thenormal action of a syringe, but may also inject or remove fluid viascrew actuation once threads on the plunger and within the barrel of thesyringe have been activated. Injection via normal syringe plunging, butfluid removal only via screw actuation allows for rapid inflation of theballoon, but carefully titrated removal of fluid based upon the pitch ofthe thread on the plunger.

In one embodiment, processor 702 may identify via sensors 106 when apatient requires more intravenous fluids, and communicate with andinstruct an external pump to provide IV fluids to the patient. Inanother embodiment, processor 702 may identify via sensors 106 whenincreases or decreases in vasopressor medications are needed, andcommunicate with and instruct an external pump to adjust the amount ofvasopressors administered to the patient.

Referring to FIG. 8, an exemplary external central processing unitconstructed in accordance with the principles of the present disclosureis described. As shown in FIG. 8, external central processing unit 800comprises processor 802 having memory 804 and communication circuitry806. In FIG. 8, components of processor 802 are not depicted to scale oneither a relative or absolute basis. Processor 802 may be constructedsimilarly to processor 702 of catheter controller unit 700 of FIG. 7,such that processor 802 may be operatively coupled to sensors 106,receive data indicative of the measured physiological information fromsensors 106, and compare the measured physiological information with atarget physiological range stored in memory 804. When system 100comprises external central processing unit 800, processor 802 ofexternal central processing unit 800 determines whether the measuredphysiological information is within the target physiological range,calculates information indicative of the appropriate change in theamount of occlusion by expandable blood flow regulation device 104required to bring the patient's physiology within the targetphysiological range if the measured physiological information fallsoutside the target physiological range, and transmits the information tocatheter controller unit 700 via communication circuitry 806. Forexample, communication circuitry 806 of external central processing unit800 may transmit the information to communication circuitry 706 ofcatheter controller unit 700 via at least one of WiFi, Bluetooth,Wixel-based communication, or cellular communication, or a wiredconnection.

In one embodiment, system 100 may comprise intravenous medication pump1000. Intravenous medication pump 1000 may deliver vasoactivemedications to the patient through a peripherally placed or centrallyplaced IV. Processor 802 of external central processing unit 800 maydetermine whether the measured physiological information is within atarget physiological range associated with various physiologicparameters, e.g., blood pressure, heart rate, indices of tissueperfusion including measured blood flow, calculate informationindicative of the appropriate change in the amount of vasoactivemedications required to bring the patient's physiology within the targetphysiological range if the measured physiological information fallsoutside the target physiological range, and transmit the information tointravenous medication pump 1000 via communication circuitry 806, e.g.,via at least one of WiFi, Bluetooth, Wixel-based communication, orcellular communication, or a wired connection. Intravenous medicationpump 1000 may deliver vasoactive medications to the patient to modulate,e.g., raise or lower, patient physiology, e.g., heart rate, systemicblood pressure or pressure within discreet regions of the body, bloodflow in the aorta, or other markers including mathematical relationshipsderived therefrom, based on the information received from externalcentral processing unit 800. In one embodiment, intravenous medicationpump 1000 may include its own processor operatively coupled to sensors106 such that intravenous medication pump 1000 receives data indicativeof the measured physiological information from sensors 106 directly,compares the measured physiological information with the targetphysiological range, and delivers vasoactive medications to the patientbased on the comparison.

In one embodiment, system 100 may comprise intravenous fluid pump 1100.Intravenous fluid pump 1100 may deliver fluids and/or blood products tothe patient through a peripherally placed or centrally placed IV.Processor 802 of external central processing unit 800 may determinewhether the measured physiological information is within a targetphysiological range associated with various physiologic parameters,e.g., blood pressure, heart rate, indices of tissue perfusion includingmeasured blood flow, calculate information indicative of the appropriatechange in the amount of vasoactive medications required to bring thepatient's physiology within the target physiological range if themeasured physiological information falls outside the targetphysiological range, and transmit the information to intravenous fluidpump 1100 via communication circuitry 806, e.g., via at least one ofWiFi, Bluetooth, Wixel-based communication, or cellular communication,or a wired connection. Intravenous fluid pump 1100 may deliver fluidsand/or blood products to the patient to modulate, e.g., raise or lower,patient physiology, e.g., heart rate, systemic blood pressure orpressure within discreet regions of the body, blood flow in the aorta,or other markers including mathematical relationships derived therefrom,based on the information received from external central processing unit800. In one embodiment, intravenous fluid pump 1100 may include its ownprocessor operatively coupled to sensors 106 such that intravenous fluidpump 1100 receives data indicative of the measured physiologicalinformation from sensors 106 directly, compares the measuredphysiological information with the target physiological range, anddelivers fluids and/or blood products to the patient based on thecomparison.

Referring to FIG. 9, an exemplary method for automatically, dynamicallyregulating the degree of aortic blood flow regulation for endovascularperfusion augmentation in accordance with the principles of the presentdisclosure is described. Method 900 may be used to perform EPACC on apatient, for example, in shock from sepsis or trauma. At step 902,distal end 103 of catheter 102 is introduced into the patient via thefemoral artery or the radial artery such that expandable blood flowregulation device 104 disposed at distal end 103 is placed within theaorta. As described above, expandable blood flow regulation device 104may comprise balloon catheter 200, wire-over-balloon catheter 300, 400,intra-aortic sail catheter 500, or caged-balloon catheter 600. In oneembodiment, catheter 102 may comprise multiple expandable blood flowregulation devices such that one expandable blood flow regulation deviceis placed within a zone, e.g., zone 1, of the aorta and anotherexpandable blood flow regulation device is placed in a different zone,e.g., zone 3, of the aorta.

At step 904, expandable blood flow regulation device 104 may be expandedto regulate blood flow through the aorta. For example, drive mechanism708 of catheter controller unit 700 may cause balloon 204 of ballooncatheter 200 to be inflated such that it regulates blood flow in theaorta; balloon 304, 404 of wire-over-balloon catheter 300, 400 to beinflated such that it completely occludes the aorta, immediatelyfollowed by the tightening of wires 306, 406 to indent balloon 304, 404such that it only partially occludes the aorta; wire framework 502 to beexpanded such that thin membrane 504 only partially occludes the aorta;and/or compliant inner balloon 606 to be inflated such that it extrudesthrough windows 604 of non-compliant outer balloon 602 to only partiallyoccludes the aorta.

At step 906, sensors 106 may measure physiological informationindicative of blood flow through the aorta. For example, as describedabove, sensors 106 may measure information indicative of blood pressure,heart rate, central venous pressure, peripheral vascular resistance,respiratory rate, pulmonary pressures, and intracranial pressure.Sensors 106 may comprise one or more sensors positioned proximal and/ordistal to each expandable blood flow regulation device utilized toeffectively monitor patient physiology.

At step 908, processor 702 of catheter controller unit 700, or whenexternal central processing unit 800 is utilized, processor 802, maycompare the measured physiological information with a targetphysiological range, and at step 910, determine whether the measuredphysiological information falls within the target physiological range.If it is determined at step 910 that the measured physiologicalinformation falls within the target physiological range, method 300 maymaintain the current state of expansion of expandable blood flowregulation device 104 and return to step 906 to continue measuringphysiological information of the patient. If it is determined at step910 that the measured physiological information falls outside the targetphysiological range, e.g., exceeds or falls below the targetphysiological range, catheter controller until 700 may determine theamount of change in expansion of expandable blood flow regulation device104 necessary to bring patient physiology within the targetphysiological range, and at step 912, cause drive mechanism 708 toadjust the expansion or contraction of the expandable blood flowregulation device, e.g., inflate or deflate balloon or tighten or loosenwires, to adjust the amount of blood flow through the aorta. Whenexternal central processing unit 800 is utilized, processor 802transmits informative indicative of the amount of change in expansion ofexpandable blood flow regulation device 104 necessary to bring patientphysiology within the target physiological range, determined at step910, to catheter controller unit 700 via communication circuitry 806 and706 before proceeding to step 912.

Study Comparing EPACC and Standard Critical Care

A study comparing EPACC and Standard Critical Care (STD) was approved byThe Institutional Animal Care and Use Committee at David Grant MedicalCenter, Travis Air Force Base. The study flow is outlined in FIG. 10.For example, first, healthy adult, castrate male and non-pregnant femaleYorkshire-cross swine (Sus scrofa) weighing between 60 and 95 kg wereacclimated for a minimum of 10 days prior to experimentation. Ahemorrhagic shock ischemia-reperfusion injury was created by performinga splenectomy followed by a 30-minute controlled hemorrhage of 25% oftotal blood volume. The ensuing hypotension was treated with 45 minutesof descending thoracic aortic occlusion to improve proximal hemodynamicsand induce distal body ischemia. Following the 45-minute occlusivephase, all animals were resuscitated with their shed blood beforerandomization into one of two critical care groups—STD or EPACC. STD wasprovided via an automated critical care platform that deliveredcrystalloid fluid boluses and titration of vasopressors based on apredefined critical care algorithm described in further detail below.Animals randomized to EPACC were provided with automated partial aorticocclusion of the descending thoracic aorta to maintain blood pressurewithin target range (proximal mean arterial pressure 60-70 mmHg), with aminimum aortic flow threshold of 80% of baseline aortic flow (BAF)(weight-based estimation). As will be understood by one having ordinaryskill in the art, other minimum aortic flow thresholds may be used. Forexample, lower thresholds such as 60% BAF or higher thresholds such as120%, e.g., if the patient is in a hyper dynamic (low blood pressure butvery high cardiac output). Once flow reached this threshold due toprogressive balloon inflation, no further balloon support was provided.To increase blood pressure towards the goal range in this scenario, thesame automated IV fluid and vasopressor administration algorithm as theSTD group was applied. After a total study duration of 6 hours, theanimals were sacrificed and underwent necropsy with histologic analysisof organs.

Specifically, animals were fasted for 12 hours prior to experimentation.Animals were pre-medicated with 6.6 mg/kg intramusculartiletamine/zolazepam (TELAZOL, Fort Dodge Animal Health, Fort Dodge,Iowa). Following isoflurane induction and endotracheal intubation,general anesthesia was maintained with 2% isoflurane in 100% oxygen. Allanimals received a 1 liter bolus of Plasma-Lyte (Baxter, Deerfield,Ill.) to ensure fluid optimization at the onset of the experiment. Tooffset the vasodilatory effects of general anesthesia, an intravenousinfusion of norepinephrine (0.01 mg/kg/min) was instituted upon venousaccess, and titrated prior to experimentation to achieve a target meanarterial pressure between 65 and 75 mm Hg. Animals were mechanicallyventilated to maintain end-tidal CO2 at 40±5 mm Hg. During initialsurgical preparation, plasmalyte maintenance IV fluid was administeredat a rate of 10 mL/kg/h until the abdomen was closed. After abdominalclosure maintenance fluids were continued at 5 mL/kg/h for the remainderof the study. Intravenous heparin was administered to achieve anactivated clotting time (ACT) of 100 seconds. An underbody warmer wasused to maintain core body temperature between 35 and 37° C. and ahot-air body warmer was instituted if core body temperature droppedbelow 35° C.

Following a generous laparotomy and placement of a cystotomy tube, asplenectomy was performed to minimize hemodynamic variation fromautotransfusion. The supraceliac aorta was exposed by dividing the leftdiaphragm and incising the left inferior pulmonary ligament. The aortawas dissected circumferentially for a length of 5-10 cm and two adjacentintercostal arteries were ligated. A perivascular flow probe (Transonic,Ithaca, N.Y.) was placed proximally to the two ligated intercostalarteries. Additional flow probes were placed on the right carotid arteryand the left renal artery. Following a right renal biopsy, the abdomenwas closed with cable ties. Following surgical cutdown, a 7 Fr arterialsheath (Teleflex, Morrisville, N.C.) was placed in the right commonfemoral artery, a 12 F arterial sheath (Teleflex, Morrisville, N.C.) wasplaced in the left common femoral artery. A dual lumen 10 Fr venousresuscitation line (Cook Medical, Bloomington, Ind.) was placed in theleft femoral vein for blood transfusion and resuscitation fluids.Bilateral external jugular veins were surgically exposed and cannulatedwith a 7 Fr triple lumen catheter (Cook Medical, Bloomington, Ind.) anda 7 Fr arterial sheath (Teleflex, Morrisville, N.C.) to allow formaintenance fluid and vasoactive medication administration. A 9 Frarterial sheath (Teleflex, Morrisville, N.C.) was placed in the leftaxillary artery after surgical exposure for proximal blood pressuremeasurements. The right brachial artery was exposed and cannulated witha 7 Fr sheath (Teleflex, Morrisville, N.C.) to facilitate initialhemorrhage. A CODA-LP catheter (Cook Medical, Bloomington, Ind.) wasintroduced through the left femoral 12 Fr arterial sheath and positionedjust distal to the aortic flow probe.

Physiologic measurements of proximal and distal blood pressure, aorticblood flow, renal blood flow, carotid blood flow, heart rate, centralvenous pressure, and core temperature were collected in real time with aBiopac MP150 (Biopac Corporation, Goleta, Calif.) multichannel dataacquisition system. A complete blood count and basic metabolic panelwere collected at the start of the experiment prior to euthanasia.Arterial blood gases, urine, and serum were collected routinelythroughout the experiment and urine and serum were frozen at −80° C. forlater analysis. Following euthanasia, a necropsy was performed withnotation of any gross anatomic abnormalities. Heart, lungs, brain,kidney, aorta, small and large bowel, and distal muscular tissue weresampled and fixed for pathologic and histologic analysis by aveterinarian blinded to the treatment groups. Histologic scoring wasdefined as: 0 (no evidence), 1 (minimal), 2 (minor), 3 (moderate), and 4(severe).

The automated care platform consisted of four devices capable ofwireless communication. A microprocessor within a central processingunit (CPU) received physiologic data from the BioPac data acquisitionsystem, and the CPU wirelessly transmitted instructions based onpredefined algorithms to three peripheral devices; an automated syringepump controlling an endovascular catheter, a syringe pump titrating theadministration of norepinephrine, and a peristaltic pump providing IVcrystalloid boluses.

Following blood resuscitation, the animals were randomized to either theEPACC arm or the STD arm of the experiment. Animals in the EPACC groupreceived automated endovascular support using the wireless automatedsyringe pump running custom closed loop adaptive feedback algorithms tocontrol the balloon volume of the CODA LP in Zone I of the aorta, asoutlined below.

If pMAP <60 mmHg and CVP <7 mmHg and Aortic flow >80% of weight basednormal→increase balloon supportIf pMAP <60 mmHg and CVP <7 mmHg and Aortic flow <80% of weight basednormal→decrease balloon supportIf pMAP <60 mmHg and CVP <7 mmHg and Aortic flow <80% of weight basednormal→fluid bolus and increase NE by 0.02 mcg/kg/minIf pMAP <60 mmHg and CVP 7-9 mmHg and Aortic flow <80% of weight basednormal→fluid bolus and increase NE by 0.01 mcg/kg/minIf pMAP <60 mmHg and CVP >9 mmHg and Aortic flow <80% of weight basednormal→increase NE by 0.01 mcg/kg/minIf pMAP <60 mmHg and CVP >9 mmHg and Aortic flow <80% of weight basednormal→and NE=0.2 mcg/kg/min→fluid bolusIf pMAP 60-70 mmHg do nothingIf pMAP >70 mmHg→decrease NE by 0.01 mcg/kg/min

For example, when the mean arterial proximal (pMAP) blood pressure fellbelow 60 mmHg and aortic flow exceeded 80% of BAF, endovascular supportwould be provided via partial balloon inflation. If aortic flow droppedbelow 80% of BAF, the degree of aortic occlusion was decreased byreducing balloon volume until aortic flow returned to the targetthreshold. As described above, higher or lower minimum aortic flowthresholds of BAF may be used depending on the patient's condition. Ifpersistent hypotension developed, crystalloid boluses and norepinephrinewould be provided through the standard critical care algorithm, based oncontinuous CVP and mean arterial blood pressure readings proximal to theCODA LP balloon.

Animals in the STD arm of the study were administered crystalloidboluses and had titration of vasopressor based on a standard protocol,as outlined below.

If pMAP <60 mmHg and CVP <7 mmHg→fluid bolus and increase NE by 0.02mcg/kg/minIf pMAP <60 mmHg and CVP 7-9 mmHg→fluid bolus and increase NE by 0.01mcg/kg/minIf pMAP <60 mmHg and CVP >9 mmhg→increase NE by 0.01 mcg/kg/minIf pMAP <60 mmHg and CVP >9 mmHg and NE=0.2 mcg/kg/min→fluid bolusIf pMAP 60-70 mmHg do nothingIf pMAP >70 mmHg→decrease NE by 0.01 mcg/kg/min

The target MAP range was defined as 60-70 mmHg for the critical carephase, a priori. Animals with a blood pressure greater than 70 mmHg wereweaned from vasopressor medications preferentially until initialvasopressor medication doses were met prior to having balloon supportweaned. Once vasopressor medications reached baseline rates, balloonsupport was weaned until full restoration of flow.

Data analysis was performed with STATA version 14.0 (Stata Corporation,Bryan, Tex.). Continuous variables are presented as means and standarderrors of the means if normally distributed and as medians withinterquartile ranges if not distributed normally. T-tests were used tocompare normally distributed continuous data and Wilcoxson rank sumtests were used for data that was not normally distributed. Dichotomousand categorical variables were analyzed by Chi-squared test andpresented as percentages. Statistical significance was set at p<0.05.

As shown in Table 1 below, there were no significant differences inbaseline characteristics or initial laboratory parameters between theSTD and EPACC groups.

TABLE 1 Baseline Characteristics STD (n = 6) EPACC (n = 6) P Sex 1.0Male   4 (66.7)   4 (66.7) Female   2 (33.3)   2 (33.3) Weight (kg) 77.5(8.0)  77.0 (3.5)  0.89 pH 7.4 (0.0) 7.4 (0.0) 0.94 PiO₂:FiO₂ Ratio 373(96)  409 (83)  0.50 Hemoglobin 10.3 (0.8)  10.0 (0.8)  0.49 White BloodCells 15.2 (3.0)  12.9 (1.7)  0.13 Platelets 275 (45)  292 (105) 0.73Potassium (mEq) 3.7 (0.2) 3.6 (0.2) 0.51 Lactate (mg/dL) 2.4 (0.5) 3.0(0.7) 0.14 Creatinine  1.3 (0.13) 1.4 (0.2) 0.49 Glucose 93 (8)  87 (7) 0.20 Proximal MAP (mmHg) 66 (7)  67 (8)  0.90 Aortic Flow (ml/kg) 38.3(4.9)  36.7 (9.3)  0.72Following the hemorrhage phase, both groups of animals had similardecreases in blood pressure.

As shown in Table 2 below, during aortic occlusion, there were nosignificant differences in maximum proximal MAP or average proximal MAP(pMAP-proximal mean arterial pressure; dMAP-distal mean arterialpressure).

TABLE 2 Hemodynamics Between Treatment Groups STD (n = 6) EPACC (n = 6)p-value Min. pMAP Hemorrhage (mmHg) 33 (29-36) 31 (26-37) 0.63 Ave. pMAPIntervention (mmHg) 129 (105-151) 113 (101-123) 0.20 Max. pMAPIntervention (mmHg) 161 (141-182) 152 (142-160) 0.15 Average pMAPCritical Care (mmHg) 60 (57-63) 65 (64-66) <0.01 Time at Goal pMAPCritical Care (%) 51.0 (29.5-72.6) 95.3 (93.2-97.4) <0.01 Ave. dMAPCritical Care (mmHg) 55 (51-59) 42 (38-46) <0.01 Ave. Aortic FlowCritical Care (ml/min) 3960 (3176-4743) 2680 (2376-2984) 0.01 Ave.Aortic Flow Critical Care (mL/kg/min) 51 (41-61) 35 (32-38) <0.01

During the critical care phase, animals in the EPACC group had a higheraverage MAP (EPACC 65 mmHg, 95CI 64-66; STD 60 mmHg, 95CI 57-63;p<0.01), a lower distal MAP (EPACC 42 mmHg, 95CI 38-46; STD 55 mmHg,95CI 51-59; p<0.01) and a lower aortic flow (EPACC 35 ml/kg/min, 95CI32-38; STD 51 ml/kg/min, 95CI 41-46; p=0.01), as shown in FIGS. 11 and12. As shown in FIG. 11, EPACC animals remained within goal proximal MAPduring critical care for a greater period of time when compared to theSTD animals (EPACC 95.3%, 95CI 93.2-97.4; STD 51.0%, 95CI 29.5-72.6;p<0.01).

Referring to FIG. 12, and as shown in Table 3 below, immediately afterballoon deflation there were no significant differences in the maximumlactate (STD 9.6 mg/dL, 95CI 8.5-10.7; EPACC 9.8 mg/dL, 95CI 9.1-10.6;p=0.87).

TABLE 3 Interventions and laboratory values between groups STD (n = 6)EPACC (n = 6) p-value Maximum Lactate (mg/dL) 9.6 (8.5-10.7) 9.8(9.1-10.6) 0.87 Total Resuscitation Boluses (ml) 7400 (6148-8642) 1583(12-3154) <0.01 Total Resuscitation Boluses (ml/kg) 96 (76-117) 21(0-42) <0.01 Final PiO₂:FiO₂ Ratio 259 (103-414) 320 (234-405) 0.63Final Creatinine (mg/dL) 1.7 (1.4-2.0) 2.3 (2.1-2.5) <0.01 Final Lactate(mg/dL) 5.2 (3.7-6.8)) 4.7 (4.1-5.3) 0.52 Hypoglycemic Episode During 4(66.7%) 1 (16.7%) 0.08 Critical Care (%)

During the critical care portion of the study, the EPACC animalsrequired less intravenous crystalloids when compared to the STD group(EPACC 21 ml/kg mg/dL, 95CI 0-42; STD 96 ml/kg, 95CI 76-117; p<0.01),required a lower dose of norepinephrine (EPACC 5 mcg/kg/min, 95CI 0-16;STD 51 mcg/kg/min, 95CI 37-64; p<0.01), and the EPACC group had a lowerincidence of hypoglycemic episodes during the critical care phase of thestudy (EPACC 1 of 6 animals, 16.7%; STD 4 of 6 animals, 66.7%, p=0.08),as shown in FIG. 13.

As shown in FIG. 13, by the end of the study, there were no differencesin final lactate or final P:F ratio, but animals in the EPACC group hada higher creatinine (EPACC 2.3 mg/dL, 95CI 2.1-2.5; STD 1.7 mg/dl, 95CI1.4-2.0; p<0.01). In addition, there were no differences in the ratio ofurine N-Gal to serum N-Gal between groups (EPACC 76.0%, 95CI 0-185.1;STD 53.7%, 95CI 0-132). Animals in the EPACC group had more edema withinthe kidneys on histological analysis (EPACC 2, IQR 2-2; STD 0.5 IQR 0-2,p=0.02), but there were no differences in the amount of cellular damageon direct visualization (EPACC 2, IQR 0-3; STD 0, IQR 0-2, p=0.16).There were no differences in the histologic analysis of small bowel,large bowel, or spinal cord.

The intent of this study was to determine if partial augmentation ofproximal blood pressure using an automated endovascular aortic ballooncatheter in a model of vasodilatory shock could serve as a resuscitativeadjunct by improving hemodynamics to the heart, lung, and brain whilemaintaining adequate flow to clear distal ischemic metabolites andperfuse distal vascular beds. The feasibility of this approach wasdemonstrated using an automated syringe pump precisely controllingballoon volume in response to proximal blood pressure and aortic flow.Using an aggressive threshold for endovascular support, improvements influids and vasopressor requirements have been demonstrated withoutincreasing the overall ischemic burden. EPACC improved both the averageblood pressure proximal to the balloon as well as the duration of timewithin the predefined target blood pressure range despite having similarblood pressure goals and fluid and vasopressor resuscitationrequirements. Although serum creatinine was increased with EPACC, therewere no differences in the extent of renal injury on histologicanalysis.

Vasodilatory shock from ischemia reperfusion injuries is common afterprocedures requiring complete aortic occlusion. Similar to septic shockstates, patients are often unresponsive to initial early interventionsand may require large volumes of crystalloid infusions and high doses ofvasopressor medications to optimize perfusion to the heart and brain.Often, these interventions themselves can be harmful, leading topulmonary edema, heart failure, cerebral edema, and ischemia to distalorgans and limbs from excessive vasoconstriction. In the most extremecases, a patient's cardiovascular system can be unresponsive to anyintervention. This refractory state leads to persistent hypotension,electrolyte and glucose metabolism abnormalities, multi-organ ischemia,and death. While the clinical consensus on the resuscitation algorithmsand medications used to treat shock are continually refined, there hasbeen no recent innovation proposed for refractory states. In thesescenarios, EPACC may be a viable adjunct. Endovascular techniques andtools have improved greatly over the past 20 years with a steady advancetowards smaller devices and greater functionality. For example, small 7Fr catheters are now being used routinely to arrest hemorrhage inexsanguinating trauma patients with promising results. The developmentof these low profile catheters has paved the way for endovasculartechniques as an adjunct to standard critical care resuscitation.

Using a vasodilatory hyperdynamic model of shock partial aorticocclusion has been demonstrated to augment proximal pressure anddecrease resuscitation requirements while maintaining a sufficient levelof distal perfusion to clear ischemic metabolites at a rate similar tostandard critical care. With the exception of cardiac and neurogenicshock, most types of shock exhibit a hyperdynamic cardiac output stateafter even minimal intravascular volume restoration. This increasedcardiac demand can be undermined by poor coronary artery perfusionduring a diastolic filling period that is characterized by low diastolicblood pressures. Therefore, excessive cardiac output is not onlyinsufficient to perfuse distal tissues and minimize ischemia but alsoresults in increased cardiac work in the setting of compromised coronaryperfusion. This vicious cycle can lead to cardiovascular collapse.

Current therapeutic adjuncts for shock states can only address globalhemodynamics, and therefore large amounts of crystalloids and high dosesof vasopressors may be required before perfusion to the heart isoptimized. EPACC offers a novel intervention to augment standardcritical care. Although distal aortic flow is attenuated by EPACC, theanimals were still able to clear the large lactate burden as well as theSTD group. This result suggests that excessive aortic flow aboveweight-based norms to distal tissue beds does not necessarily hastenclearance of ischemic by-products. This is a critical finding whenunderstanding the potential safety of this novel therapy, namely thatattenuating aortic flow back to a normal pre-injury level with EPACCdoes not result in additional ischemia to injured tissues. In essence, ahyperemic aortic flow state in response to ischemia is not necessarilybeneficial and may actually represent a pathologic response to injury.Conversely, this suggests that attenuating aortic flow with EPACCtowards a more physiologic range in the context of a hyperdynamiccardiac state may be of benefit by reducing overall cardiac work withoutincurring additional distal ischemic debt.

Beyond attenuated aortic flow, EPACC inherently produces a lower meanarterial pressure below the level of partial occlusion. In this study,EPACC animals consistently demonstrated a significantly lower bloodpressure distal to the balloon compared to conventional critical care.This finding suggests that the distal pressures maintained with EPACCwere sufficient to clear ischemic metabolites and that traditionaldiastolic blood pressure goals of greater than 65 mmHg for shock may notbe required to maintain adequate tissue perfusion after source controlhas been achieved.

In settings of severe vasodilatory shock, maintaining adequate bloodpressure is often difficult despite mobilizing maximal resources andeffort for an individual patient. We have demonstrated that even withsimilar blood pressure goals, EPACC was able to improve the average meanarterial blood pressure throughout the period of critical care whencompared to STD. These findings may be the result of two separatephenomenon noted with EPACC. First, EPACC is capable of nearinstantaneous adjustments of balloon volume on a second-to-second basisin response to blood pressure fluctuations. Unlike the administration ofintravenous crystalloids or intravenous vasopressor medications thattake time to be delivered and have their effect, the mechanicalaugmentation of blood pressure is instantaneous. Thus, the greaterprecision of EPACC interventions combined with their rapid effect resultin numerous minute adjustments that create hemodynamic consistency. Thislikely accounts for the greater percentage of time within the targetblood pressure range seen with EPACC. The second possible explanationfor the improved hemodynamics within the EPACC group is a preferentialeffect on the coronary artery perfusion that arises from increasedafterload near the aortic root that is achieved without increasingarteriolar vasoconstriction with vasopressors. Therefore, EPACC mayoffer a critical adjunct to IV fluids and vasopressors by optimizingcoronary perfusion.

In addition to its general applicability to shock, EPACC may also have adistinct role in the resuscitation of ischemia-reperfusion injuries(IRI) following aortic occlusion by controlling the washout of distalischemic metabolites. Although a multisystem trauma victim with IRI is afairly specific patient, the advent of REBOA for trauma is increasingthe incidence of IRI from the profound distal ischemia. These ischemictissues manifest inflammatory cytokines, but can also result inhyperkalemia during reperfusion with resultant cardiac depression. Whileboth groups of animals in the present study had profound IRI, EPACCcontrolled distal flow for the majority of the critical care phase asevidenced by lower aortic flow rates. This gradual return to baselineaortic flow rates may have slowed the washout of ischemic metabolitesand served to minimize ongoing injury that occurs as a direct result ofreperfusion of damaged tissues. Prior work has demonstrated that duringischemia and reperfusion, the injury to the tissue beds are a result ofnot only the initial ischemia, but also of the reaction of the ischemictissues to the reintroduction of oxygenated blood. This reintroductionof oxygen into tissues results in the rapid development of reactiveoxygen species, opening of the MPT pore of mitochondria that werealready damaged during the original ischemia, an influx of calcium intothe cell, routine endothelial dysfunction with increased vasodilation,and the generation of a larger inflammatory response. It remains unclearat this time whether a slower reintroduction of oxygenated blood todistal tissues will be beneficial, or the nuances of when and how thatreintroduction should occur. Nevertheless, the present studydemonstrates that EPACC has the functionality to tightly control distalreperfusion. This controlled reintroduction of flow may ultimately serveto minimize the reperfusion injury that ensues.

The resuscitation of a critically ill patient represents a significantdemand on medical facilities, consuming physical resources as well ascognitive capacity. Not only is this demand substantial in the moment,but is frequently sustained for extended periods. In resource limitedenvironments, a single critically ill patient can overwhelm availableresources, precluding high quality care in the context of multiplecritically ill patients. Therefore, strategies to minimize utilizationof these scarce resources will inherently enable higher quality care formore patients. EPACC addresses several of these key consideration forcritical care environments. First, EPACC may limit reliance on largevolume crystalloid administration and the need for prolonged infusion ofvasoactive agents. This is of particular relevance for care in resourcepoor scenarios, where the ability to maintain large volumes ofcrystalloid or vasoactive drugs is not feasible. Second, through the useof automation, EPACC can provide maintenance of hemodynamics without thereliance on continuous involvement of the provider, effectivelyoffloading the cognitive requirements needed to care for criticallyinjured patients. This affords the opportunity to provide sustained highlevel care to multiple patients simultaneously. Finally, this technologyenables transitions of care or transport of patients without the needfor extensive resources. This applies to scenarios of prolonged criticalcare transport from rural medical facilities or austere militaryenvironments.

While great improvements have been made in the care of critically illpatients through protocolized algorithms, human error and systemconstraints still result in failure to adequately resuscitate. Forexample, a patient who cannot tolerate large fluid boluses issusceptible to heart failure or pulmonary edema, while failing toprovide sufficient intravascular volume to optimize cardiovascularperformance is equally as deleterious.

The development of EPACC for critical care has been driven by thedeveloping need for minimized material requirements for the prolongedfield care scenarios that can exist for military physicians andpractitioners, and therefore an aggressive amount of mechanical pressureaugmentation was chosen in an attempt to maximize the material benefit,while potentially incurring some ongoing distal ischemia. This strategywhere fluid administration is not initiated until native aortic flow isless than 80% of weight based norms resulted in a dramatic reduction influid and vasopressor requirements, but was met with increasingcreatinine. The increase in creatinine was not associated with a changein histology between groups or an difference in the urine:serum n-galconcentration—a marker of direct renal injury. The increase in creatinemay be secondary to the expected decrease in renal blood flow andsubsequent decrease in filtration. A small but not significant increasein the urine:serum n-gal ratio may also be early evidence of renalinjury that is either not yet apparent given the short duration of thestudy or not significant due to the small number of animals in thestudy. Future long term survival studies as well as dose response curvesto establish the optimal minimum aortic flow threshold beyond whichfluid and vasopressor administration are re-instated are necessary tofully realize the potential and safety of EPACC.

There are several limitations to the current study. First, this was alimited survival study with a total experimental time of only 6 hours.Many physiologic consequences of trauma and from interventions are oftendelayed. It may be that critical differences between groups with respectto physiology or histology would manifest with studies of longerduration. A second limitation is that only a single “dose” of EPACC wastested in this study. Like any intervention, EPACC can be adjusted inthe amount of balloon support provided prior to the addition ofintravenous fluids or vasopressors. For this study, a “dose” of 80% ofweight adjusted baseline aortic flow was chosen. However, as describedabove, other minimum aortic flow thresholds may be used depending on thespecific patient's condition. Finally, only one shock state was testedin this study. It is possible that the shock state fromischemia-reperfusion is distinct from other etiologies of shock.Therefore, future studies are needed to fully understand the potentialutility of endovascular support for other types of shock such as septicshock. These limitations notwithstanding, the current manuscript is thefirst description of a fully automated critical care platform thatincorporates endovascular support in order to minimize materialrequirements for patients in shock from ischemia reperfusion injury.Furthermore, it represents a novel therapeutic approach to patients inrefractory shock and may prove advantageous in lesser degrees ofphysiologic derangement to minimize the morbidity and mortalityassociated with conventional treatments.

Thus, the addition of EPACC versus an automated critical care platformalone significantly reduced material requirements for resuscitationwhile increasing both the average proximal MAP and the duration of timeat goal blood pressure. Although EPACC did result in a higher serumcreatinine concentration by the end of the study, there were nodifferences in markers of renal injury or histology between groups.

While various illustrative embodiments of the disclosure are describedabove, it will be apparent to one skilled in the art that variouschanges and modifications may be made therein without departing from thedisclosure. The appended claims are intended to cover all such changesand modifications that fall within the true scope of the disclosure.

1. An automated endovascular perfusion augmentation system, the systemcomprising: a catheter having a proximal end portion and a distal endportion, the distal end portion configured for placement within an aortaof a patient; an expandable aortic blood flow regulation device disposedon the distal end portion of the catheter for placement within theaorta, the expandable aortic blood flow regulation device configured toexpand to restrict blood flow through the aorta and to contract; acatheter controller unit coupled to the proximal end portion of thecatheter and configured to cause the expandable aortic blood flowregulation device to expand and contract in the aorta; one or moresensors configured to measure physiological information indicative ofblood flow through the aorta; and a non-transitory computer readablemedia having instructions stored thereon, wherein the instructions, whenexecuted by a processor coupled to the one or more sensors, cause theprocessor to compare the measured physiological information with atarget physiological range such that the catheter controller unitautomatically adjusts expansion and contraction of the expandable aorticblood flow regulation device to adjust an amount of blood flow throughthe aorta if the measured physiological information falls outside thetarget physiological range.
 2. The system of claim 1, wherein theexpandable aortic blood flow regulation device comprises a balloonconfigured to be inflated to expand to restrict blood flow through theaorta, and wherein the catheter controller unit comprises a syringe pumpconfigured to inflate or deflate the balloon to adjust the amount ofblood flow through the aorta if the measured physiological informationfalls outside the target physiological range.
 3. The system of claim 1,wherein the expandable aortic blood flow regulation device comprises: aballoon configured to be inflated to occlude blood flow through theaorta; and one or more wires configured to surround the balloon, the oneor more wires further configured to be tightened to indent the balloonto permit blood flow around the balloon, wherein the catheter controllerunit comprises a syringe pump configured to inflate or deflate theballoon, and wherein the catheter controller unit is further configuredto shorten or lengthen the one or more wires to tighten or loosen theone or more wires surrounding the balloon to adjust the amount of bloodflow through the aorta if the measured physiological information fallsoutside the target physiological range.
 4. The system of claim 3,wherein the catheter controller unit shortens or lengthens the one ormore wires via at least one of a stepper motor or a motorized armconfigured to shorten or lengthen the one or more wires against a fixedpoint on the catheter.
 5. The system of claim 1, wherein the expandableaortic blood flow regulation device comprises: a wire frameworkconfigured to radially expand or contract from a center axis of thecatheter; and an aortic blood flow regulation sail comprising a thinmembrane, the aortic blood flow regulation sail configured to surround aportion of the wire framework, wherein the catheter controller unit isconfigured to shorten or lengthen the wire framework to radially expandor contract the aortic blood flow regulation sail to adjust the amountof blood flow through the aorta if the measured physiologicalinformation falls outside the target physiological range.
 6. The systemof claim 5, wherein the catheter controller unit shortens or lengthensthe wire framework via at least one of a stepper motor or a motorizedarm configured to shorten or lengthen the wire framework against a fixedpoint on the catheter.
 7. The system of claim 1, wherein the expandableaortic blood flow regulation device comprises: a non-compliant balloonhaving one or more windows; and a compliant balloon configured to beenclosed within the non-compliant balloon, wherein the cathetercontroller unit comprises a syringe pump configured to inflate ordeflate the compliant balloon such that the compliant balloon isextruded through the one or more windows of the non-compliant balloon toadjust the amount of blood flow through the aorta if the measuredphysiological information falls outside the target physiological range.8. The system of claim 1, wherein one of the one or more sensors isdisposed on the catheter distal to the expandable aortic blood flowregulation device and is configured to measure physiological informationindicative of blood pressure in the aorta distal to the expandableaortic blood flow regulation device.
 9. The system of claim 1, whereinone of the one or more sensors is disposed on the catheter proximal tothe expandable aortic blood flow regulation device and is configured tomeasure physiological information indicative of blood pressure in theaorta proximal to the expandable aortic blood flow regulation device.10. The system of claim 1, wherein the one or more sensors areconfigured to measure physiological information indicative of blood flowthrough the aorta including at least one of heart rate, respiratoryrate, aortic blood flow proximal or distal to the expandable aorticblood flow regulation device, blood temperature, pressure within theexpandable aortic blood flow regulation device, cardiac output of thepatient, carotid blood flow, pulmonary pressures, peripheral vascularresistance, or intracranial pressure.
 11. The system of claim 1, whereinthe one or more sensors are configured to measure physiologicalinformation indicative of blood flow through the aorta by measuring atleast one of lactate level, cortisol level, reactive oxygen specieslevel, or pH, of a fluid of the patient.
 12. The system of claim 1,further comprising a second expandable aortic blood flow regulationdevice disposed on the distal end portion of the catheter proximal tothe expandable aortic blood flow regulation device for placement withinthe aorta, the second expandable aortic blood flow regulation devicecoupled to the catheter controller unit and configured to expand torestrict blood flow through the aorta and to contract, wherein theexpandable aortic blood flow regulation device and the second expandableaortic blood flow regulation device are configured to be spaced apartsuch that the expandable aortic blood flow regulation device is placedin a zone of the aorta, and the second expandable aortic blood flowregulation device is placed in a different zone of the aorta.
 13. Thesystem of claim 12, wherein at least one of the one or more sensors ispositioned distal to the expandable aortic blood flow regulation device,in between the expandable aortic blood flow regulation device and thesecond expandable aortic blood flow regulation device, or proximal tothe second expandable aortic blood flow regulation device.
 14. Thesystem of claim 1, further comprising an external central processingunit operatively coupled to the one or more sensors and the cathetercontroller unit, the external central processing unit comprising theprocessor and configure to transmit information indicative of whetherthe measured physiological information falls outside the targetphysiological range to the catheter controller unit.
 15. The system ofclaim 14, wherein the external central processing unit transmits theinformation to the catheter controller unit via at least one of WiFi,Bluetooth, Wixel-based communication, or cellular communication.
 16. Thesystem of claim 1, further comprising an automated pump configured todeliver intravenous medication to the patient, wherein the instructions,when executed by the processor coupled to the one or more sensors, causethe processor to compare the measured physiological information with atarget physiological range such that the automated pump deliversintravenous medications to the patient to modulate patient physiologybased on the comparison.
 17. The system of claim 1, further comprisingan automated pump configured to deliver intravenous fluids and bloodproducts to the patient, wherein the instructions, when executed by theprocessor coupled to the one or more sensors, cause the processor tocompare the measured physiological information with a targetphysiological range such that the automated pump delivers intravenousfluids or blood products to the patient to modulate patient physiologybased on the comparison.
 18. A method for automatically, dynamicallyregulating the degree of aortic blood flow regulation for endovascularperfusion augmentation, the method comprising: introducing a distal endportion of a catheter comprising an expandable aortic blood flowregulation device within an aorta of a patient; expanding the expandableaortic blood flow regulation device to restrict blood flow through theaorta; measuring physiological information indicative of blood flowthrough the aorta via one or more sensors; comparing the measuredphysiological information with a target physiological range; andadjusting expansion and contraction of the expandable aortic blood flowregulation device to adjust an amount of blood flow through the aorta ifthe measured physiological information falls outside the targetphysiological range.
 19. The method of claim 18, wherein the expandableaortic blood flow regulation device comprises a balloon configured to beinflated to expand to restrict blood flow through the aorta, and whereinexpanding or contracting the expandable aortic blood flow regulationdevice comprises inflating or deflating the balloon via a syringe pump.20.-22. (canceled)
 23. The method of claim 18, wherein measuringphysiological information indicative of blood flow through the aorta viaone or more sensors comprises measuring at least one of heart rate,respiratory rate, aortic blood flow proximal or distal to the expandableaortic blood flow regulation device, blood temperature, pressure withinthe expandable aortic blood flow regulation device, cardiac output ofthe patient, carotid blood flow, pulmonary pressures, peripheralvascular resistance, or intracranial pressure.
 24. (canceled)